Growth of Escherichia coli ceases when nutrients are depleted or when secreted waste products accumulate to high levels. Under these conditions the bacteria initiate a complex developmental plan to allow extended survival. In the lab this stationary phase of the bacterial life cycle can be achieved by starvation for a single essential nutrient such as a carbon source, phosphate, or nitrogen in the form of ammonia. Implementation of the stationary phase developmental plan requires the alternate sigma factor RpoS.Previously we have identified an orphan response regulator SprE (also known as RssB or MviA). In rapidly growing cells, SprE directs RpoS for destruction by the ATP-dependent protease CIpP/X, thus maintaining this sigma factor at low levels. SprE activity is inhibited when cells are starved for carbon, and RpoS levels quickly rise. We have also shown that RpoS stimulates sprE expression. Paradoxically this regulatory feedback loop results in high levels of SprE in stationary phase cells when the protein is presumably inactive. Using a combination of genetics and biochemistry we will define the signal transduction pathway that controls SprE activity, and we will probe the functional significance or this regulatory feedback loop. We will also determine the signal transduction mechanisms responsible for the development of stationary phase when cells are starved for phosphate or ammonia, and we will determine how cells integrate the conflicting signals that can arise when cells are starved for only one of these elements. Stationary phase raises several questions of fundamental importance. Cells sense and respond to impending starvation. How do they know they are about to deplete the medium of one essential nutrient when all other essential nutrients are abundant? How are conflicting signals integrated? Finally, since RpoS is important for the pathogenesis of several bacteria, an understanding of this complex signal transduction network may reveal chinks in the armor of these pathogens.